Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo analysis.
BACKGROUND
Obesity in postmenopausal women is associated with increased breast cancer risk, development of more aggressive tumors and resistance to certain anti-breast cancer treatments. Some of these effects might be mediated by obesity hormone leptin, acting independently or modulating other signaling pathways. Here we focused on the link between leptin and HER2. We tested if HER2 and the leptin receptor (ObR) can be coexpressed in breast cancer cell models, whether these two receptors can physically interact, and whether leptin can transactivate HER2. Next, we studied if leptin/ObR can coexist with HER2 in breast cancer tissues, and if presence of these two systems correlates with specific clinicopathological features.


METHODS
Expression of ObR, HER2, phospho-HER2 was assessed by immunoblotting. Physical interactions between ObR and HER2 were probed by immunoprecipitation and fluorescent immunostaining. Expression of leptin and ObR in breast cancer tissues was detected by immunohistochemistry (IHC). Associations among markers studied by IHC were evaluated using Fisher's exact test for count data.


RESULTS
HER2 and ObR were coexpressed in all studied breast cancer cell lines. In MCF-7 cells, HER2 physically interacted with ObR and leptin treatment increased HER2 phosphorylation on Tyr 1248. In 59 breast cancers, the presence of leptin was correlated with ObR (the overall association was about 93%). This result was confirmed both in HER2-positive and in HER2-negative subgroups. The expression of leptin or ObR was numerically more frequent in larger (> 10 mm) tumors.


CONCLUSIONS
Coexpression of HER2 and the leptin/ObR system might contribute to enhanced HER2 activity and reduced sensitivity to anti-HER2 treatments.
Fiorio
Elena
E
Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, USA. elena.fiorio@univr.it
Mercanti
Anna
A
Terrasi
Marianna
M
Micciolo
Rocco
R
Remo
Andrea
A
Auriemma
Alessandra
A
Molino
Annamaria
A
Parolin
Veronica
V
Di Stefano
Bruno
B
Bonetti
Franco
F
Giordano
Antonio
A
Cetto
Gian Luigi
GL
Surmacz
Eva
E
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics; D017698:Postmenopause / Q000235:genetics; D011485:Protein Binding; D020239:Receptor Cross-Talk; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D015533:Transcriptional Activation
D020738:Leptin; D018719:Erb-b2 Receptor Tyrosine Kinases; D054411:Receptors, Leptin; C515448:LEPR protein, human